The diagnosis of familial hypercholesterolemia (hyperbetalipoproteinemia) is presently based on plasma lipid and lipoprotein phenotype and a monogenic mode of inheritance. In the absence of specific biochemical markers, genetic heterogeneity cannot be ruled out and our studies indicate that several variants of FH can be distinguished based on clinical, laboratory and genetic studies. In 1973, we reported that cultured skin fibroblasts from a phenotypically defined group of patients with "monogenic" hypercholesterolemia had a derangement in the feedback inhibition of cholesterol synthesis by medium lipids. The assay is able to discriminate between "homozygotes", "heterozygotes" and "normals", and yields normal results in patients with hypertriglyceredemic hyperlipidemias. Goldstein and Brown have reported similar and more extensive findings. Our recent studies have revealed a different pattern of biochemical abnormality in two other variants of hypercholesterolemic families. We propose to explore further the biochemical defects in cultured fibroblasts in different variants of FH and assess their value in the diagnosis and classification of hereditary hyperlipoproteinemias. The patient population in Lebanon represents a unique opportunity for such a study. To date we have studied 38 families with 68 children who developed extensive xanthomatosis in the first decade and had a mean plasma cholesterol of 750 mg/100 ml. We have also studied several large kindreds with variant forms of FH who have milder manifestations of the disorder. The principal investigator, who is visiting professor at the American Univerisity of Beirut, is actively engaged in the study and management of these patients. Studies done at the American University of Beirut will aim at a characterization of the clinical and laboratory features in these families and the biochemical studies on cultured fibroblasts will be done at CMDNJ-Rutgers Medical School.